Forkhead transcription factor FOXO subfamily is essential for reactive oxygen species-induced apoptosis

Intracellular accumulation of reactive oxygen species is implicated in the pathogenesis of cancer and other diseases by disturbing proper cell cycle control or cell survival. Here, we show that the expression and phosphorylation of FOXO is drastically affected by H(2)O(2) treatment, resulting in drastic induction of luteal cell apoptosis. Western blot analysis revealed that FOXO1a accumulated preferentially in the nucleus upon ROS stimuli, resulting in the transactivation of IRS promoter activity driven by H(2)O(2)-activated FOXO1a. Because ROS-induced cell death was suppressed by co-transfection of a FOXO3a mutant that lacks the activation-domain of transcription, transactivation of pro-apoptotic genes by FOXO was necessary to cause ROS-induced apoptosis. In fact, expression of several pro-apoptotic genes, such as Bim and BCL-6 was induced in H(2)O(2)-stimulated cells, and was blocked by co-transfection of dominant-negative type FOXO3a mutant. These findings indicate that FOXO is a key regulator of ROS-induced apoptosis in mammalian cells.